The NHS health check programme in England: a qualitative study.

Despite an extensive evidence-base linking patterns of health with social determinants, recent public health policy has emphasized 'lifestyle diseases' and risk factor modification through behavioural and pharmacological intervention. In England, one manifestation of this has been the launch of the National Health Service Health Check programme. This paper reports findings from a small-scale qualitative study exploring experiences of engaging with a community-based health check in Knowsley, England, among 17 males and 19 females, with varying levels of risk for cardiovascular disease, who agreed to be contacted for the purpose of research at the time they underwent their check. Analysis revealed that the community-based nature of the checks provided opportunities for people to find out more about their health who might not otherwise have done so. Participants expressed a range of responses to the communication of the risk score, often revealing their confusion about its meaning. Changes in behaviour were identified, which participants connected with having had a check. This study raises questions about where, how and by whom health checks are delivered. Emphasis on health checks reflects the dominant individualist ideology, but this study also suggests that the process provides opportunities to enable and empower individuals, albeit in small ways. However, they remain a 'downstream' approach to public health, emphasizing medical and behavioural options for risk factor reduction rather than focussing on primary prevention through changes to the wider environment. Furthermore, although developed as a central feature of the UK's strategy to reduce health inequalities, health checks may widen them.

Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926).

Recent evidence suggests that blocking aberrant hedgehog pathway signaling may be a promising therapeutic strategy for the treatment of several types of cancer. Cyclopamine, a plant Veratrum alkaloid, is a natural product antagonist of the hedgehog pathway. In a previous report, a seven-membered D-ring semisynthetic analogue of cyclopamine, IPI-269609 (2), was shown to have greater acid stability and better aqueous solubility compared to cyclopamine. Further modifications of the A-ring system generated three series of analogues with improved potency and/or solubility. Lead compounds from each series were characterized in vitro and evaluated in vivo for biological activity and pharmacokinetic properties. These studies led to the discovery of IPI-926 (compound 28), a novel semisynthetic cyclopamine analogue with substantially improved pharmaceutical properties and potency and a favorable pharmacokinetic profile relative to cyclopamine and compound 2. As a result, complete tumor regression was observed in a Hh-dependent medulloblastoma allograft model after daily oral administration of 40 mg/kg of compound 28.

Semisynthetic cyclopamine analogues as potent and orally bioavailable hedgehog pathway antagonists.

Herein is reported the synthesis of a novel class of hedgehog antagonists derived from cyclopamine. The acid sensitive D-ring of cyclopamine was homologated utilizing a sequence of chemoselective cyclopropanation and stereoselective acid-catalyzed rearrangement. Further modification of the A/B-ring homoallylic alcohol to the conjugated ketone led to the discovery of new cyclopamine analogues with improved pharmaceutical properties and in vitro potency (EC 50) ranging from 10 to 1000 nM.